tbuckley/cabot-search huggingface dataset:
Differential requirement of Hippo cascade during CTNNB1 or AXIN1 mutation‐driven hepatocarcinogenesis
Authors: Binyong Liang, Haichuan Wang, Yu Qiao, Xue Wang, Manning Qian, Xinhua Song, Yi Zhou, Yi Zhang, Runze Shang, Li Che, Yifa Chen, Zhiyong Huang, Hong Wu, Satdarshan P. Monga, Yong Zeng, Diego F. Calvisi, Xiaoping Chen, Xin Chen
Journal: Hepatology (2022)

Background and Aims: Gain‐of‐function (GOF) mutations of CTNNB1 and loss‐of‐function (LOF) mutations of AXIN1 are recurrent genetic alterations in hepatocellular carcinoma (HCC). We aim to investigate the functional contribution of Hippo/YAP/TAZ in GOF CTNNB1 or LOF AXIN1 mutant HCCs. Approach and Results: The requirement of YAP/TAZ in c‐Met/β‐Catenin and c‐Met/sgAxin1‐driven HCC was analyzed using conditional Yap , Taz , and Yap;Taz knockout (KO) mice. Mechanisms of AXIN1 in regulating YAP/TAZ were investigated using AXIN1 mutated HCC cells. Hepatocyte‐specific inducible TTR‐CreER T2 KO system was applied to evaluate the role of Yap;Taz during tumor progression. Cabozantinib and G007‐LK combinational treatment were tested in vitro and in vivo . Nuclear YAP/TAZ was strongly induced in c‐Met/sgAxin1 mouse HCC cells. Activation of Hippo via overexpression of Lats2 or concomitant deletion of Yap and Taz significantly inhibited c‐Met/sgAxin1 driven HCC development, whereas the same approaches had mild effects in c‐Met/β‐Catenin HCCs. YAP is the major Hippo effector in c‐Met/β‐Catenin HCCs, and both YAP and TAZ are required for c‐Met/sgAxin1‐dependent hepatocarcinogenesis. Mechanistically, AXIN1 binds to YAP/TAZ in human HCC cells and regulates YAP/TAZ stability. Genetic deletion of YAP/TAZ suppresses already formed c‐Met/sgAxin1 liver tumors, supporting the requirement of YAP/TAZ during tumor progression. Importantly, tankyrase inhibitor G007‐LK, which targets Hippo and Wnt pathways, synergizes with cabozantinib, a c‐MET inhibitor, leading to tumor regression in the c‐Met/sgAxin1 HCC model. Conclusions: Our studies demonstrate that YAP/TAZ are major signaling molecules downstream of LOF AXIN1 mutant HCCs, and targeting YAP/TAZ is an effective treatment against AXIN1 mutant human HCCs.
Activation of pyroptosis by specific organelle-targeting photodynamic therapy to amplify immunogenic cell death for anti-tumor immunotherapy
Authors: Shuang Zeng, Chen Chen, Liuwei Zhang, Xiaosheng Liu, Ming Qian, Hongyan Cui, Jingyun Wang, Qixian Chen, Xiaojun Peng
Journal: Bioactive Materials (2022)

Pyroptosis, a unique lytic programmed cell death, inspired tempting implications as potent anti-tumor strategy in pertinent to its potentials in stimulating anti-tumor immunity for eradication of primary tumors and metastasis. Nonetheless, rare therapeutics have been reported to successfully stimulate pyroptosis. In view of the intimate participation of reactive oxygen species (ROS) in stimulating pyroptosis, we attempted to devise a spectrum of well-defined subcellular organelle (including mitochondria, lysosomes and endoplasmic reticulum)-targeting photosensitizers with the aim of precisely localizing ROS (produced from photosensitizers) at the subcellular compartments and explore their potentials in urging pyroptosis and immunogenic cell death (ICD). The subsequent investigations revealed varied degrees of pyroptosis upon photodynamic therapy (PDT) towards cancerous cells, as supported by not only observation of the distinctive morphological and mechanistic characteristics of pyroptosis, but for the first-time explicit validation from comprehensive RNA-Seq analysis. Furthermore, in vivo anti-tumor PDT could exert eradication of the primary tumors, more importantly suppressed the distant tumor and metastatic tumor growth through an abscopal effect, approving the acquirement of specific anti-tumor immunity as a consequence of pyroptosis. Hence, pyroptosis was concluded unprecedently by our proposed organelles-targeting PDT strategy and explicitly delineated with molecular insights into its occurrence and the consequent ICD.
Endoscopy International Open – recently published
Journal: Endoscopy (2018)

Comment on: Comparative analysis of ESD versus EMR in a large European series of non-ampullary superficial duodenal tumorsEndosc Int Open 2018; 06(08): E1008-E1014DOI: 10.1055/a-0577-7546 Comment on: Novel triple lumen catheter for ERCP tissue diagnosisEndosc Int Open 2018; 06(08): E984-E988DOI: 10.1055/a-0591-2740 Comment on: The efficacy of the pocket-creation method for cases with severe fibrosis in colorectal endoscopic submucosal dissectionEndosc Int Open 2018; 06(08): E975-E983DOI: 10.1055/a-0593-5818
Trial of Cinpanemab in Early Parkinson’s Disease
Authors: Anthony E. Lang, Andrew D. Siderowf, Eric A. Macklin, Werner Poewe, David J. Brooks, Hubert H. Fernandez, Olivier Rascol, Nir Giladi, Fabrizio Stocchi, Caroline M. Tanner, Ronald B. Postuma, David K. Simon, Eduardo Tolosa, Brit Mollenhauer, Jesse M. Cedarbaum, Kyle Fraser, James Xiao, Karleyton C. Evans, Danielle L. Graham, Inbal Sapir, Jennifer Inra, R. Matthew Hutchison, Minhua Yang, Tara Fox, Samantha Budd Haeberlein, Tien Dam
Journal: New England Journal of Medicine (2022)

Aggregated α-synuclein plays an important role in Parkinson's disease pathogenesis. Cinpanemab, a human-derived monoclonal antibody that binds to α-synuclein, is being evaluated as a disease-modifying treatment for Parkinson's disease.In a 52-week, multicenter, double-blind, phase 2 trial, we randomly assigned, in a 2:1:2:2 ratio, participants with early Parkinson's disease to receive intravenous infusions of placebo (control) or cinpanemab at a dose of 250 mg, 1250 mg, or 3500 mg every 4 weeks, followed by an active-treatment dose-blinded extension period for up to 112 weeks. The primary end points were the changes from baseline in the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score (range, 0 to 236, with higher scores indicating worse performance) at weeks 52 and 72. Secondary end points included MDS-UPDRS subscale scores and striatal binding as assessed on dopamine transporter single-photon-emission computed tomography (DaT-SPECT).Of the 357 enrolled participants, 100 were assigned to the control group, 55 to the 250-mg cinpanemab group, 102 to the 1250-mg group, and 100 to the 3500-mg group. The trial was stopped after the week 72 interim analysis owing to lack of efficacy. The change to week 52 in the MDS-UPDRS score was 10.8 points in the control group, 10.5 points in the 250-mg group, 11.3 points in the 1250-mg group, and 10.9 points in the 3500-mg group (adjusted mean difference vs. control, -0.3 points [95% confidence interval {CI}, -4.9 to 4.3], P = 0.90; 0.5 points [95% CI, -3.3 to 4.3], P = 0.80; and 0.1 point [95% CI, -3.8 to 4.0], P = 0.97, respectively). The adjusted mean difference at 72 weeks between participants who received cinpanemab through 72 weeks and the pooled group of those who started cinpanemab at 52 weeks was -0.9 points (95% CI, -5.6 to 3.8) for the 250-mg dose, 0.6 points (95% CI, -3.3 to 4.4) for the 1250-mg dose, and -0.8 points (95% CI, -4.6 to 3.0) for the 3500-mg dose. Results for secondary end points were similar to those for the primary end points. DaT-SPECT imaging at week 52 showed no differences between the control group and any cinpanemab group. The most common adverse events with cinpanemab were headache, nasopharyngitis, and falls.In participants with early Parkinson's disease, the effects of cinpanemab on clinical measures of disease progression and changes in DaT-SPECT imaging did not differ from those of placebo over a 52-week period. (Funded by Biogen; SPARK ClinicalTrials.gov number, NCT03318523.).
Monoclonal Antibody Therapy in Parkinson’s Disease — The End?
Authors: Alan Whone
Journal: New England Journal of Medicine (2022)

Parkinson’s disease is increasing in incidence at a faster rate than any other serious neurologic condition.1 Despite multiple agents putatively showing preclinical promise, there is no disease-modifying therapy available for clinical use in this disorder. Indeed, no potential treatment has survived scrutiny in a clinical trial to reach approval by a regulatory body. Several target mechanisms have been identified by which to achieve neuroprotection or neurorestoration of dopaminergic neurons that are at the nexus of Parkinson’s disease. One approach, which engendered much hope, has been the targeting of the pathologically aggregated form of the protein α-synuclein.2 Studies of active immunotherapy . . .
Trial of Prasinezumab in Early-Stage Parkinson’s Disease
Authors: Gennaro Pagano, Kirsten I Taylor, Judith Anzures-Cabrera, Maddalena Marchesi, Tanya Simuni, Kenneth Marek, Ronald B Postuma, Nicola Pavese, Fabrizio Stocchi, Jean-Philippe Azulay, Brit Mollenhauer, Lydia López-Manzanares, David S Russell, James T Boyd, Anthony P Nicholas, María R Luquin, Robert A Hauser, Thomas Gasser, Werner Poewe, Benedicte Ricci, Anne Boulay, Annamarie Vogt, Frank G Boess, Juergen Dukart, Giulia D'Urso, Rebecca Finch, Stefano Zanigni, Annabelle Monnet, Nathalie Pross, Andrea Hahn, Hanno Svoboda, Markus Britschgi, Florian Lipsmeier, Ekaterina Volkova-Volkmar, Michael Lindemann, Sebastian Dziadek, Štefan Holiga, Daria Rukina, Thomas Kustermann, Geoffrey A Kerchner, Paulo Fontoura, Daniel Umbricht, Rachelle Doody, Tania Nikolcheva, Azad Bonni
Journal: New England Journal of Medicine (2022)

Aggregated α-synuclein plays an important role in the pathogenesis of Parkinson’s disease. The monoclonal antibody prasinezumab, directed at aggregated α-synuclein, is being studied for its effect on Parkinson’s disease.
Monoclonal Antibodies — A Different Approach to Combat Malaria
Authors: Johanna P. Daily
Journal: New England Journal of Medicine (2022)

In 2020, a total of 241 million cases of malaria and 627,000 malaria-related deaths were reported.1 In this issue of the Journal, Wu and colleagues2 present a new approach to provide immune protection with a next-generation monoclonal antibody against Plasmodium falciparum malaria infection, the most prevalent and deadly type of malaria. Therapeutic monoclonal antibodies target a specific antigen, provide high specificity and safety, and are routinely used in medical practice to treat cancer and autoimmune diseases, and recently they have been used to prevent Covid-19.3,4 Wu et al. conducted VRC 614, a phase 1 clinical trial to test the safety, . . .
A Zoonotic Henipavirus in Febrile Patients in China
Authors: Xiao-Ai Zhang, Hao Li, Fa-Chun Jiang, Feng Zhu, Yun-Fa Zhang, Jin-Jin Chen, Chee-Wah Tan, Danielle E Anderson, Hang Fan, Li-Yan Dong, Chang Li, Pan-He Zhang, Yue Li, Heng Ding, Li-Qun Fang, Lin-Fa Wang, Wei Liu
Journal: New England Journal of Medicine (2022)
Diagnostic Aspirations
Authors: Hannah X. Chen, Manuela Cernadas, Sara O. Vargas, Bruce D. Levy, Joseph Loscalzo
Journal: New England Journal of Medicine (2022)

A 63-year-old woman presented with dyspnea and cough. She had been in her usual state of health until 2 days earlier, when myalgias and dyspnea with ambulation developed, followed by a cough productive of green sputum.
Reply to Campagna and Caci: Taking for Granted Conclusions from Studies that Cannot Prove Causality of Respiratory Symptoms and Vaping
Authors: Jonathan D. Klein
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

"Reply to Campagna and Caci: Taking for Granted Conclusions from Studies that Cannot Prove Causality of Respiratory Symptoms and Vaping." American Journal of Respiratory and Critical Care Medicine, 206(12), pp. 1569–1570
Effect of pneumococcal conjugate vaccines and SARS-CoV-2 on antimicrobial resistance and the emergence of Streptococcus pneumoniae serotypes with reduced susceptibility in Spain, 2004–20: a national surveillance study
Authors: Julio Sempere, Mirella Llamosí, Beatriz López Ruiz, Idoia del Río, Covadonga Pérez-García, Darío Lago, Mercedes Gimeno, Pilar Coronel, Fernando González-Camacho, Mirian Domenech, Jose Yuste
Journal: The Lancet Microbe (2022)

Epidemiological studies are necessary to explore the effect of current pneumococcal conjugate vaccines (PCVs) against antibiotic resistance, including the rise of non-vaccine serotypes that are resistant to antibiotics. Hence, epidemiological changes in the antimicrobial pattern of Streptococcus pneumoniae before and during the first year of the COVID-19 pandemic were studied.In this national surveillance study, we characterised the antimicrobial susceptibility to a panel of antibiotics in 3017 pneumococcal clinical isolates with reduced susceptibility to penicillin during 2004-20 in Spain. This study covered the early and late PCV7 periods; the early, middle, and late PCV13 periods; and the first year of the COVID-19 pandemic, to evaluate the contribution of PCVs and the pandemic to the emergence of non-vaccine serotypes associated with antibiotic resistance.Serotypes included in PCV7 and PCV13 showed a decline after the introduction of PCVs in Spain. However, an increase in non-PCV13 serotypes (mainly 11A, 24F, and 23B) that were not susceptible to penicillin promptly appeared. A rise in the proportion of pneumococcal strains with reduced susceptibility to β-lactams and erythromycin was observed in 2020, coinciding with the emergence of SARS-CoV-2. Cefditoren was the β-lactam with the lowest minimum inhibitory concentration (MIC)50 or MIC90 values, and had the highest proportion of susceptible strains throughout 2004-20.The increase in non-PCV13 serotypes associated with antibiotic resistance is concerning, especially the increase of penicillin resistance linked to serotypes 11A and 24F. The future use of PCVs with an increasingly broad spectrum (such as PCV20, which includes serotype 11A) could reduce the impact of antibiotic resistance for non-PCV13 serotypes. The use of antibiotics to prevent co-infections in patients with COVID-19 might have affected the increased proportion of pneumococcal-resistant strains. Cefotaxime as a parenteral option, and cefditoren as an oral choice, were the antibiotics with the highest activity against non-PCV20 serotypes.The Spanish Ministry of Science and Innovation and Meiji-Pharma Spain.For the Spanish translation of the abstract see Supplementary Materials section.
Mapping local variation in household overcrowding across Africa from 2000 to 2018: a modelling study
Authors: Michael G Chipeta, Emmanuelle P A Kumaran, Annie J Browne, Bahar H Kashef Hamadani, Georgina Haines-Woodhouse, Benn Sartorius, Robert C Reiner, Christiane Dolecek, Simon I Hay, Catrin E Moore
Journal: The Lancet Planetary Health (2022)

Household overcrowding is a serious public health threat associated with high morbidity and mortality. Rapid population growth and urbanisation contribute to overcrowding and poor sanitation in low-income and middle- income countries, and are risk factors for the spread of infectious diseases, including COVID-19, and antimicrobial resistance. Many countries do not have adequate surveillance capacity to monitor household overcrowding. Geostatistical models are therefore useful tools for estimating household overcrowding. In this study, we aimed to estimate household overcrowding in Africa between 2000 and 2018 by combining available household survey data, population censuses, and other country-specific household surveys within a geostatistical framework.We used data from household surveys and population censuses to generate a Bayesian geostatistical model of household overcrowding in Africa for the 19-year period between 2000 and 2018. Additional sociodemographic and health-related covariates informed the model, which covered 54 African countries.We analysed 287 surveys and population censuses, covering 78 695 991 households. Spatial and temporal variability arose in household overcrowding estimates over time. In 2018, the highest overcrowding estimates were observed in the Horn of Africa region (median proportion 62% [IQR 57-63]); the lowest regional median proportion was estimated for the north of Africa region (16% [14-19]). Overall, 474·4 million (95% uncertainty interval [UI] 250·1 million-740·7 million) people were estimated to be living in overcrowded conditions in Africa in 2018, a 62·7% increase from the estimated 291·5 million (180·8 million-417·3 million) people who lived in overcrowded conditions in the year 2000. 48·5% (229·9 million) of people living in overcrowded conditions came from six African countries (Nigeria, Ethiopia, Democratic Republic of the Congo, Sudan, Uganda, and Kenya), with a combined population of 538·3 million people.This study incorporated survey and population censuses data and used geostatistical modelling to estimate continent-wide overcrowding over a 19-year period. Our analysis identified countries and areas with high numbers of people living in overcrowded conditions, thereby providing a benchmark for policy planning and the implementation of interventions such as in infectious disease control.UK Department of Health and Social Care, Wellcome Trust, Bill & Melinda Gates Foundation.
Neuropsychiatric risk in children with intellectual disability of genetic origin: IMAGINE, a UK national cohort study
Authors: Jeanne Wolstencroft, Francesca Wicks, Ramya Srinivasan, Sarah Wynn, Tamsin Ford, Kate Baker, Samuel J R A Chawner, Jeremy Hall, Marianne B M van den Bree, Michael J Owen, Jeanne Wolstencroft, Francesca Wicks, Ramya Srinivasan, Marie Erwood, Amy Lafont, Husne Timur, Zheng Ye, Susan Walker, Frida Printzlau, Manoj Juj, Sarah Davies, Hayley Denyer, Alice Watkins, Eleanor Kerry, Nadia Coscini, Nasrtullah Fatih, Anna Lucock, Spiros Denaxas, William Mandy, Neil Walker, Sarah Wallwork, Eleanor Dewhurst, Andrew Cuthbert, Aimee Challenger, Sophie Andrews, Peter Holmans, Samantha Bowen, Karen Bradley, Philippa Birch, Molly Tong, Nicola Lewis, Sinead Ray, Matthew Sopp, Hayley Moss, Sarah Wynn, Beverley Searle, Lisa Robertson, Jonathan Berg, Anne Lampe, Shelagh Joss, Paul Brennan, Alison Kraus, Nayana Lahiri, Astrid Weber, Myfanwy Rawson, Diana Johnson, Pradeep Vasudevan, Rachel Harrison, Denise Williams, Eamonn Maher, Usha Kini, Fleur Van Dijk, Virginia Clowes, Jana Gurasashvilli, Sahar Mansour, Muriel Holder-Espinasse, Amy Watford, Julia Rankin, Diana Baralle, Annie Procter, Tamsin Ford, Kate Baker, Samuel Chawner, Jeremy Hall, Marianne B M Van den Bree, Michael J Owen, David Skuse, F Lucy Raymond, David Skuse, F Lucy Raymond
Journal: The Lancet Psychiatry (2022)

Children with intellectual disability frequently have multiple co-morbid neuropsychiatric conditions and poor physical health. Genomic testing is increasingly recommended as a first-line investigation for these children. We aim to determine the effect of genomics, inheritance, and socioeconomic deprivation on neuropsychiatric risk in children with intellectual disability of genetic origin as compared with the general population.
Evidence gaps and diversity among potential win–win solutions for conservation and human infectious disease control
Authors: Skylar R Hopkins, Kevin D Lafferty, Chelsea L Wood, Sarah H Olson, Julia C Buck, Giulio A De Leo, Kathryn J Fiorella, Johanna L Fornberg, Andres Garchitorena, Isabel J Jones, Armand M Kuris, Laura H Kwong, Christopher LeBoa, Ariel E Leon, Andrea J Lund, Andrew J MacDonald, Daniel C G Metz, Nicole Nova, Alison J Peel, Justin V Remais, Tara E Stewart Merrill, Maya Wilson, Matthew H Bonds, Andrew P Dobson, David Lopez Carr, Meghan E Howard, Lisa Mandle, Susanne H Sokolow
Journal: The Lancet Planetary Health (2022)

As sustainable development practitioners have worked to “ensure healthy lives and promote well-being for all” and “conserve life on land and below water”, what progress has been made with win–win interventions that reduce human infectious disease burdens while advancing conservation goals? Using a systematic literature review, we identified 46 proposed solutions, which we then investigated individually using targeted literature reviews. The proposed solutions addressed diverse conservation threats and human infectious diseases, and thus, the proposed interventions varied in scale, costs, and impacts. Some potential solutions had medium-quality to high-quality evidence for previous success in achieving proposed impacts in one or both sectors. However, there were notable evidence gaps within and among solutions, highlighting opportunities for further research and adaptive implementation. Stakeholders seeking win–win interventions can explore this Review and an online database to find and tailor a relevant solution or brainstorm new solutions.
The transcription factor FoxP3 can fold into two dimerization states with divergent implications for regulatory T cell function and immune homeostasis
Authors: Fangwei Leng, Wenxiang Zhang, Ricardo N. Ramirez, Juliette Leon, Yi Zhong, Lifei Hou, Koichi Yuki, Joris van der Veeken, Alexander Y. Rudensky, Christophe Benoist, Sun Hur
Journal: Immunity (2022)

FoxP3 is an essential transcription factor (TF) for immunologic homeostasis, but how it utilizes the common forkhead DNA-binding domain (DBD) to perform its unique function remains poorly understood. We here demonstrated that unlike other known forkhead TFs, FoxP3 formed a head-to-head dimer using a unique linker (Runx1-binding region [RBR]) preceding the forkhead domain. Head-to-head dimerization conferred distinct DNA-binding specificity and created a docking site for the cofactor Runx1. RBR was also important for proper folding of the forkhead domain, as truncation of RBR induced domain-swap dimerization of forkhead, which was previously considered the physiological form of FoxP3. Rather, swap-dimerization impaired FoxP3 function, as demonstrated with the disease-causing mutation R337Q, whereas a swap-suppressive mutation largely rescued R337Q-mediated functional impairment. Altogether, our findings suggest that FoxP3 can fold into two distinct dimerization states: head-to-head dimerization representing functional specialization of an ancient DBD and swap dimerization associated with impaired functions.